IE63302B1 - Cyclic amine compounds and their use - Google Patents

Cyclic amine compounds and their use

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Publication number
IE63302B1
IE63302B1 IE14290A IE14290A IE63302B1 IE 63302 B1 IE63302 B1 IE 63302B1 IE 14290 A IE14290 A IE 14290A IE 14290 A IE14290 A IE 14290A IE 63302 B1 IE63302 B1 IE 63302B1
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formula
group
defined above
acid
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IE14290A
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IE900142L (en
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Giichi Goto
Hidefumi Yukimasa
Tetsuji Imamoto
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Takeda Chemical Industries Ltd
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Publication of IE63302B1 publication Critical patent/IE63302B1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
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    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing aromatic rings
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    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
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    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D211/26—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
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    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D211/30—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by doubly bound oxygen or sulfur atoms or by two oxygen or sulfur atoms singly bound to the same carbon atom
    • C07D211/32—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by doubly bound oxygen or sulfur atoms or by two oxygen or sulfur atoms singly bound to the same carbon atom by oxygen atoms
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/68—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
    • C07D211/70—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
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    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/36—Radicals substituted by singly-bound nitrogen atoms
    • C07D213/38—Radicals substituted by singly-bound nitrogen atoms having only hydrogen or hydrocarbon radicals attached to the substituent nitrogen atom
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    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/44—Radicals substituted by doubly-bound oxygen, sulfur, or nitrogen atoms, or by two such atoms singly-bound to the same carbon atom
    • C07D213/46—Oxygen atoms
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    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/56—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles

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Abstract

A cyclic amine compound of the formula wherein B means a saturated or unsaturated 5- to 7-membered aza-heterocyclic group which may be substituted; A means a bond or an alkylene or alkenylene group which may be substituted by hydrocarbon residues, oxo, hydroxyimino, and/or hydroxy, ___ means either a single bond or a double bond (provided that when A means a bond, ___ means a single bond); R2 and R3 independently mean a hydrogen atom or a hydrocarbon residue which may be substituted (provided that both of R2 and R3 are not hydrogen atoms) or jointly form a cyclic amino group together with the adjacent nitrogen atom, n is 0, 1 or 2 and p is 1 or 2 or a physiologically acceptable salt thereof. The compounds are useful for therapy of cerebral edema, acute symptoms in cerebral apoplexy and protection of brain and nerve cell, or useful as anticholinesterase or as brain function-improving agent.

Description

Cyclic Amine Compounds and Their Use The present invention relates to pharmaceutical agents and more particularly to novel cyclic amine compounds which are effective in treating various symptoms due to brain hypoxia or ischemia, particularly cerebral edema.
The current therapeutic modality for the cerebral edema associated with increased intracranial pressure due to compression by a brain neoplasm or trauma or that associated with cerebral ischemia comprises a massive administration of corticosteroids and the ethylene glycol therapy utilizing its osmotic pressure but no therapeutic drug is available that is satisfactory in efficacy or in the aspect of side effects.
The object of the present invention is to provide a novel class of compounds which are useful as therapeutic drugs for cerebral edema.
The inventors of the present invention explored compounds which could be of use as medicament for improving the functions of the central nervous system and particularly compounds of value for the relief of cerebral edema due to brain ischemia and succeeded in the creation of compounds of the formula wherein B means a saturated or unsaturated 5- to 7membered aza-heterocyclic group which may be substituted; A means a bond or a two- or three-valent aliphatic hydrocarbon residue which may be substituted by hydrocarbon residues, oxo, hydroxyimino and/or hydroxy; — means either a single bond or a double bond (provided that when A means a bond, — means a single bond); R2 and R3 independently mean a hydrogen atom'.or·.a hydrocarbon residue which may be substituted (provided that both of. R2 and R3 are not hydrogen atoms) or jointly form a cyclic amino group together with the adjacent nitrogen atom; n'is 0, 1 or 2; and p is 1 or 2 [hereinafter referred to sometimes as compound (I)) and salts thereof. It was found that these compounds and salts have very potent ameliorative effects on cerebral edema. Accordingly, the inventors conducted further research and accomplished the present invention.
The present invention is, therefore, directed, in one aspect, to a cyclic amine compound of formula (I) as well as a salt thereof and, in another aspect, to a therapeutic agent for cerebral edema, acute symptoms in cerebral apoplexy or stroke and a brain/nerve cell protecting agent, both containing said compound or salt.
Thus, the present invention relates to a cyclic amine compound of the formula XR,'- means a group of the formula: cr ^\2_/ wherein is ® a hYdro9en atom, alkyl, C2_4 alkenyl or C2_4 alkynyl group be substituted by a halogen, Ct_3 alkoxy, © a ?l-6 which may cyano, amino, mono- or di-C^.g alkylamino, 5- to 7-membered cyclic amino or hydroxy, © an aryl group selected from phenyl and naphthyl or an aralkyl group selected from benzyl, diphenyl methyl , phenyl ethyl, naphthylmethy1 and naphthyl ethyl which may be substituted on the ring by one to three substituents selected from the group consisting of a Cj_3 alkoxy, Cj^.3 alkyl, cyano, amino, mono- or di- C^_g alkylamino, 5- to 7-mejTibered cyclic amino, hydroxy, nitro and halogen and on the alkyl moiety of the aralkyl group may be substituted by oxo or hydroxy, or ©a C2-6 alkylcarbonyl, C2_8 alkyloxycarbonyl or benzyl oxycarbonyl which may be substituted by one to three substituents selected from the group consisting of a halogen, amino and primary or secondary amino having Ci_g alkyl substituent(s), m is 0, 1 or 2; A means a bond or a two- or three-valent aliphatic hydrocarbon residue which may be substituted by hydrocarbon residues, oxo, hydroxyimino, and/ot hydroxy; -- - - means either a single bond or a double bond (provided that when A means a bondmeans a single bond); R2 and R3 independently mean, © a hydrogen atom, (2) a C!_6 alkyl, C2_4 alkenyl or C2-4 alkynyl group which may be substituted by a halogen, Ci_3 alkoxy, cyano, amino, mono- or di-C|_g alkylamino, 5- to 7-membered cyclic amino or hydroxy, or (3) an aryl group selected ^rom phenyl and naphthyl or an aralkyl group selected from benzyl, dipheny1methy1 , phenylethyl, naph thy1 methy1 and naphthyl ethyl which may be. substituted on the ring by one to three substituents selected from the group consisting of a Cj_3 alkoxy, Ci_3 alkyl, cyano, amino, mono- -or di- Ci_6 alkylamino, 5- to 7-membered cyclic amino, hydroxy, nitro and halogen and on the alkyl moiety of the aralkyl group may be substituted by oxo or hydroxy (provided that both of R2 and R3 are not hydrogen atoms) or jointly form a cyclic amino group together with the adjacent nitrogen atom; n is 0, 1 or 2 and p is 1 or 2 or a physiologically acceptable salt thereof.
It has been further found that among various species of compound (I), the compounds in which B is a 5- to 7-membered aza-heterocyclic group substituted by a benzyl group (which itself may be substituted) in the Ν’-position additionally have potent anticholinesterase activity.
In the aspect of the therapy of cerebral edema, disturbance of microcirculation in the brain (e.g. increase in erythrocyte deformability) and acute symptoms in cerebral apoplexy and a protection of neuronal cell death or- cholinesterase inhibitory action, among the compounds·(I), particularly preferred are the compounds of the formula wherein Rj is a hydrogen atom or a benzyl group which may be substituted, Ί is an integer of 0 to 4 and D' is a group of the formula -C-, -CH- or -CH2II I OH and R2' and R3' are independently a Ci.6alkyl group or jointly form a cyclic amino group together with the adjacent nitrogen atom [hereinafter referred to sometimes as compound (I')] and salts thereof.
Referring, now, to formula (I), the saturated or unsaturated 5- to 7-membered aza-heterocyclic group which may be substituted, denoted by B, includes various nitrogen-containing 5- to 7-membered heterocycles, saturated and unsaturated. Particularly desirable heterocycles include, among others, saturated or unsaturated 5- through 7-membered heterocycles each containing one nitrogen atom such as those represented by the formula z wherein Ri is a hydrogen atom, a hydrocarbon residue which may be substituted or an acyl group which may be substituted and m is 0, 1 or 2. Furthermore, among various heterocyclic groups which may be chosen for B, one which is bound to -A- in a position other than the N-position of the ring, that is to say a carbon position, is preferred.
Hereinafter, the saturated and unsaturated rings mentioned above will sometimes be designated by the formula In this connection, Rx means said hydrogen atom, hydrocarbon residue which may be substituted or acyl group which may be substituted only when the ring is attached to -A- in a position other than the Imposition, that is to say in a carbon position, and is either saturated or partially unsaturated without involvement of N.
Referring to Rj in the formula (I')/ Ri is a hydrogen atom or a benzyl group among the definition of R.
The hydrocarbon residue of the hydrocarbon residue which may be substituted as denoted by Rlz R2 and R3 and that as a substituent group on the alkylene or alkenylene group which may be substituted by hydrocarbon residues, oxo and/or hydroxy as denoted by A includes, among others, Ct.e alkyl groups (e.g. methyl, ethyl, propyl, butyl, hexyl, 4-methylpentyl, etc.), C2.4 alkenyl groups such as vinyl, allyl, 2butenyl, etc., C2.4 alkynyl groups such as propargyl, 2butynyl, etc., aryl groups such as phenyl, naphthyl, etc., and aralkyl groups such as benzyl, diphenylmethyl, phenylethyl, naphthyImethyl and naphthylethyl. The aryl or aralkyl group (including the benzyl group, as denoted by Ri) for Rj, Rz and R3 may have 1 to 3 substituents on the ring, such as, for example, Ci.3 alkoxy groups (e.g. methoxy, ethoxy), C[.3 alkyl groups (e.g. methyl, ethyl, propyl), cyano, amino, mono- or di-Ci.6alkylamino; 5- to 7-membered cyclic amino, hydroxy, nitro, halogens (e.g. chlorine, fluorine, bromine) and so on. The alkyl moiety of said aralkyl group may be substituted by oxo or hydroxy.
The substituent groups which may substitue the alkyl, alkenyl and alkynyl groups mentioned for Ru R2 and R3 include, among others, the above-mentioned halogen, C:.3 alkoxy cyano, amino, mono- or di-Cj_6 alkylamino, 5- to 7-membered cyclic amino and hydroxy.
The acyl moiety of the acyl group which may be substituted, denoted by Rj, includes carboxylic acid acyl groups (e.g. C2.6 alkylcarbonyl groups such as acetyl, propionyl, butyryl, etc.) and substituted oxycarbonyl groups (e.g. C2.8 alkyl- or aralkyloxycarbonyl groups such as methoxycarbonyl, tert-butoxvcarbonyl, benzyloxycarbonyl, etc.), for instance.
The substituent groups which may substitute such acyl groups include, among others, halogens (e.g. iodine, bromine, fluorine, chlorine), amino, and primary or secondary amino having alkyl substituents (e.g. methyl, ethyl, propyl, hexyl). The acyl groups may respectively have 1 to 3, preferably 1 to 2, such substituents.
The cyclic amino group which is formed by R2 and R3, and R2' and R3' together with the adjacent nitrogen atom includes various nitrogen-containing 5- through 7 membered heterocyclic groups, such as those of the formula /A '—'\ A25 those of the formula / R* R< formula o’ and those of the formula those of the A R« <2 In the above formulas, s is 0, 1 or 2, t is 1 or 2; R4 is a hydrogen atom or a substituent group which may substitute the cyclic amino group formed by R2 and R3, which substituent group may for example be Ci_3 alkyl (e.g. methyl, ethyl, propyl), alkylcarbonyl (e.g. acetyl, propionyl, butyryl), oxo, hydroxy, phenyl, benzyl, diphenyImethyl or amino. The two- or threevalent hydrocarbon residue which may be substituted by hydrocarbon residues, oxo, hydroxyimino or/and hydroxy which is denoted by A is preferably exemplified by Cj.6 alkylene or -alkenylene chains and methine.
OH I -CH2C-, Examples of A include -CH2 -, -CH-, -C-, -CH2CH2-, -CH2CH2C-, -CH=CH-(CH2)2- and =CH-. Preferred types of compound (I) include the following, for instance.
Rt is preferably a hydrogen atom, a Ci_4 alkyl group or a benzyl group which may be substituted, and more desirably a hydrogen atom, a alkyl group or a benzyl group which may be substituted. Compounds in which Rt is a benzyl group tend to be superior in terms of anticholinesterase activity and those in which Ri is a hydrogen atom or an alkyl group tend to be superior in terms of therapeutic efficacy for cerebral edema. Preferably, Rr and R3 independently mean a Ct.4 alkyl group or phenyImethyl, or jointly constitute a cyclic amino group together with the adjacent nitrogen atom. More desirably, R2 and R3 independently mean a alkyl group or a group of the formula where s is 0, 1 or 2 and R4 means hydrogen, phenyl or benzyl. Preferably, B is piperidyl, pyrrolidyl, pyrrolyl or pyridyl. Particularly preferred is piperidyl. Preferably, A is hydroxymethylene, a group of the formula Rs\ I \ (where R5 and R6 respectively mean a hydrogen I ' Re/q atom or a alkyl group; q is 1 or 2; and the total number of carbon atoms is not more than 6) or a group of the formula -(CH2),£C- (wherein I is an integer of 0 J to 4; this group is attached to the benzene ring through -C-).
More desirably, A is methylene, hydroxymethylene or -CH2CH2C-. Preferably, m is 1 or 2, and more desirably, m is 1. Preferably, n is 0 or 1, and more desirably n is 0.
Particularly the compounds in which B is an Nbenzyl-substituted piperidinyl group are satisfactory in anticholinesterase activity.
The more desirable compounds, in terms of anticholinesterase activity, are compounds of the formula (I) wherein Rf is a benzyl group and D' is CO-, that is, compounds of the formula z (cH,)2co- (I”) wherein 2, R2' and R3' are as defined hereinbefore [hereinafter referred to as compound (I)] and the salts thereof.
In the aspect of the therapy of cerebral edema, disturbance of microcirculation in the brain (e.g. increase in erythrocyte deformability) and acute symptoms in cerebral apoplexy or stroke, and a protection of neuronal cell death and the like, more preferable are compounds of the formula (I') wherein Rf is a hydrogen atom and 2 is 0, that is, compounds of the formula [hereinafter referred to as compound (I')] wherein D' Rf and Rf are as defined above, and the salts thereof.
Particularly, the compounds of the formula (I') wherein Rf is a hydrogen atom, 2 is 0 and D' is -CH2-, and the salts thereof are particularly useful in terms of therapeutic efficacy for cerebral edema and acute symptoms in stroke.
The compounds according to the present invention may be provided not only as the compounds of the formula (I) but also in the form of an acid addition salts, thereof particularly a physiologically acceptable acid addition salt. Examples of such acid addition salt include inorganic acid salts (e.g. salts with hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, hydrobromic acid) and organic acid salts (e.g. salts with acetic acid, propionic acid, fumaric acid, maleic acid, tartaric acid, citric acid, malic acid, oxalic acid, benzoic acid, methanesulfonic acid, benzenesulfonic acid).
The processes for production of the compound of the present invention are described below.
Among the specific compounds of formula (I) according to the present invention, compounds of the formula la) wherein R7 means a substituent group in the N-position when the ^7^1 -1/ ring is saturated, and means an acyl group which may be substituted, which is included in the definition of Rt; D means either a bond or an Ci_5 alkylene group which may be substituted by hydrocarbon residues, oxo or/and hydroxy; R2, R3, m and p are respectively as defined hereinbefore [these compounds are collectively referred to as compound (la)] can each be produced by reacting, for example, a compound of formula (II) wherein·.D, R7 and m are respectively as defined herein- ίί before and X means a halogen (e.g. chlorine, bromine, iodine) with, for example, a compound of formula (III) wherein p is as defined hereinbefore and Y means a halogen atom (e.g. fluorine, chlorine, bromine, iodine) to give a compound of formula (IV) wherein D, R7, Y, m and p are respectively as defined above and, then, reacting this compound of formula (IV) with, for example, a compound of formula (V) 15 / R t '' H N < R 3; (v) wherein R2 and R3 are as defined hereinbefore.
The compound of formula (II) can be prepared by a known method or a method analogous thereto. For example, compound (II) can be prepared in accordance with the process described in Chemical Pharmaceutical Bulletin 34./ 3747-3761, 1986.
The reaction between compound (II) and compound (III) can be carried out by a per se known method. For example, compound (II) is reacted with compound (III), either in the absence of a solvent of in a solvent, if necessary in the presence of an acid or the like. The acid may be a Lewis acid such as aluminum chloride, zinc chloride, titanium chloride or the like. The solvent may be any of the common solvents unless it interferes with the reaction. Thus, for example, the reaction can be conducted in dichloromethane, dichloroethane, nitrobenzene, carbon disulfide or the like at a temperature of generally about -30°C to 150°C and preferably about 20 to 100°C. To each mole of compound (II), compound (III) is generally used in a proportion of about 1 to 20 moles, preferably about 2 to 5 moles. The reaction between compound (IV) and compound (V) can also be conducted by a per se known method. For example, compound (IV) is reacted with compound (V), either in the absence of a solvent or in a solvent, at a temperature of about -50°C to 300°C, preferably about 20 to 200°C. The solvent may be any of the common solvents, such as water, methanol, ethanol, propanol, chloroform, dichloromethane, benzene, toluene, xylene, acetonitrile, dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide and so on. If necessary, this reaction can be conducted in the presence of an organic base, such as pyridine, 4-dimethylaminopyridine, triethylamine, triethylenediamine, tetramethylethylenediamine, etc., an inorganic base, such as sodium hydrogen carbonate, potassium hydrogen carbonate, sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, etc., sodium hydride, potassium hydride and so on.
To each mole of compound (IV), compound (V) is used in a proportion of generally about 1 to 10 moles and preferably about 2 to 4 moles. The reaction time is generally about 1 to 48 hours and preferably about 10 to 20 hours.
Among various species of compound (I), compounds of formula (Ib) wherein D, R2, R3, m and p are respectively as defined hereinbefore, provided that the hydrogen atom in the ,te\ N-position. of ring HK ) is available only when the ring is saturated, can each be prepared by treating the above-mentioned compound (la) with an acid or a base. Thus, compound (la) is treated in an aqueous solution of mineral acid (e.g. nitric acid, hydrochloric acid, hydrobromic acid, iodic acid, sulfuric acid, etc.) or an aqueous solution of alkali metal hydroxide (e.g. sodium hydroxide, potassium hydroxide, barium hydroxide, lithium hydroxide, etc.) at a temperature of generally 10 to 150°C and preferably 50 to 100°C. Generally 10 to 100 equivalents, preferably 20 to 40 equivalents, of the acid or base is used relative to compound (la). The strength of the acid or base is preferably about 1 to 10N and preferably about 4 to 10N. Though it depends on reaction temperature, the reaction time is generally about 1 to 24 hours and preferably about 2 to 10 hours.
The compounds of formula (Ic) D -C H Ο» wherein D, R2, R3, R7, m and p are respectively as defined hereinbefore can each be prepared by reducing a compound of formula (la) by a per se known procedure. For example, compound (la) is subjected to catalytic reduction in a solvent using hydrogen in the presence of a catalyst. The solvent may be any of the common solvents for chemical reactions unless the intended reaction is adversely affected. Thus, for example, the reaction can be conducted in water, methanol, ethanol, dimethylformamide, tetrahydrofuran, dioxane or the like with the aid of a palladium, rhodium, platinum, Raney nickel or other catalyst at a temperature of generally about -10°C to 100°C and preferably about 20 to 50°C, at a hydrogen pressure of 1 to 100 atmospheres, preferably. 1 to 5 atmospheres, if necessary in the presence of an acid. The acid may be a mineral acid (e.g. hydrochloric acid, nitric acid, phosphoric acid, hydrobromic acid) or an organic acid (e.g. acetic acid, propionic acid, tartaric acid, benzoic acid, methanesulfonic acid, toluenesulfonic acid, etc.). The compound (Ic) can also be produced by treating compound (la) with a metal hydride (e.g. diisobutylaluminum hydrice, triphenyltin hydride, etc.), a metal hydrogen complex compound (e.g. lithium aluminum hydride, sodium aluminum hydride, sodium triethoxyaluminum hydride, etc.), diborane or a substituted borane (e.g. sodium borohydride). These metal hydride compounds are used in a proportion of generally 0.3 to 5 moles and preferably 1 to 2 moles per mole of compound (la). The solvent may be any of the common solvents for chemical reactions unless it interferes with the intended reaction. Thus, for example, the reaction can be carried out in a protic solvent (e.g. water, methanol, ethanol, propanol, etc.) or an aprotic solvent (e.g. ethyl ether, tetrahydrofuran, dioxane, etc.) at a temperature of -10°C to 200°C, preferably 20 to 100°C.
Compounds of formula (Id) HH wherein D, Rz, R3, m and p are respectively as defined hereinbefore can each be produced by treating a compound of formula (Ic) with an acid or a base or by reducing a compound of formula (Ib) by a per se known procedure. The acid or base which can be used in the above treatment of compound (Ic) includes mineral acids (e.g. nitric acid, hydrochloric acid, hydrobromic acid, iodic acid, sulfuric acid, etc.) and alkali metal hydroxides (e.g. sodium hydroxide, potassium hydroxide, barium hydroxide, lithium hydroxide, etc.). This treatment can be carried out in an aqueous solution of the acid or base at a temperature of 10 to 150°, preferably 50 to 100°C. The strength of the acid or base is generally about 1 to 10N and preferably 4 to 10N. Based on compound (Ic), the acid or base is generally used in a proportion of about 20 to 40 equivalents. Though it depends on the reaction temperature used, the reaction time is generally about 1 to 24 hours and preferably about 2 to 10 hours. Regarding the above mentioned per se known procedure for reducing compound (Ib), the solvent may be any of the solvents commonly used for chemical reactions unless it interferes with the intended reaction. Thus, for example, water, methanol, ethanol, dimethylformamide, tetrahydrofuran, dioxane, etc. can be mentioned. The catalyst may for example be a palladium, rhodium, platinum or Raney nickel catalyst. The reaction can be conducted in the presence of such catalyst at a temperature of about -10°C to 100°C, preferably about 20 to 50°C, under the hydrogen pressure of 1 to 100 atmospheres, preferably 1 to 5 atmospheres, if necessary in the presence of an acid. The acid may be a mineral acid (e.g. hydrochloric acid, nitric acid, phosphoric acid, hydrobromic acid, etc.) or an organic acid (e.g. acetic acid, propionic acid, tartaric acid, benzoic acid, methanesulfonic acid, toluenesulfonic acid, etc.), for instance. The compound (Id) can also be produced by treating compound (Ib) with a metal hydride (e.g. diisobutylaluminum hydride, triphenyltin hydride, etc.), a metal hydrogen complex compound (e.g. lithium aluminum hydride, sodium aluminum hydride, sodium triethoxyaluminum hydride), diborane or a substituted borane (e.g. sodium borohydride, etc.) in a solvent. The solvent may be any of the common solvents for chemical reactions unless it interferes with the intended reaction. Thus, this treatment can be carried out in a protic solvent (e.gl.water, methanol, ethanol, propanol, etc.) or an aprotic solvent (e.g ethyl ether, tetrahydrofuran, dioxane, etc.) at a temperature of generally -10°C to 200°C and preferably 20 to 100°C.
Compounds of formula (Ie) wherein D, R2, R3, R7, m and p are as defined hereinbefore can each be produced by reducing a compound of formula (la) or (Ic). The solvent to be used for this reaction may be any of the common solvents for chemical reactions unless it interferes with the reaction. Thus, for example, water, methanol, ethanol, dimethylformamide, tetrahydrofuran and dioxane may be mentioned. The reaction can be conducted in such a solvent with the aid of a catalyst, which may be a palladium, rhodium, platinum or Raney nickel catalyst, at a temperature of generally about -10°C to 100°C and preferably about 20 to 50°C, under the hydrogen pressure of 1 to 100 atmospheres, preferably 1 to 5 atmospheres, if necessary in the presence of an acid. The acid may be a mineral acid (e.g. hydrochloric acid, nitric acid, phosphoric acid, hydrobromic acid) or an organic acid (e.g. acetic acid, propionic acid, tartaric acid, benzoic acid, methanesulfonic acid).
Compounds of formula (If) in 1 < \ > n — (If) wherein D, R2, R3, m and p are respectively as defined hereinbefore can each be produced by treating compound (Ie) with an acid or a base. Thus, compound (Ie) is treated with a mineral acid (e.g. nitric acid, hydrochloric acid, hydrobromic acid, iodic acid, sulfuric acid) etc.) or an alkali metal hydroxide (e.g. sodium hydroxide, potassium hydroxide, barium hydroxide, lithium hydroxide, etc.) at a temperature of generally 10 to 150°C and preferably 50 to 100°C. The strength of the acid or base is generally about 1 to 10N and preferably about 4 to 10N. Though it depends on reaction temperature, the reaction time is generally about 1 to 24 hours and preferably about 2 to 10 hours.
Compounds of formula (Ig) wherein D, R2, R3, R7, m and p are respectively as defined hereinbefore, and R8 has the same meaning as defined for R5 and R6, namely a hydrogen atom, a hydroxy group or a Ct.3 alkyl group, can be produced by reacting a compound of formula (la) with a compound of formula (VI) R8MgZ (VI) wherein R8 is as defined above and Z means a halogen atom (e.g. chlorine, bromine, iodine) and subjecting the reaction product to catalytic reduction with hydrogen in the presence of a catalyst. The reaction between compound (la) and compound (VI) can be conducted in an aprotic solvent such as tetrahydrofuran, ethyl ether, isopropyl ether, dimethoxyethane, benzene or the like at a temperature of generally about -50°C to 100°C and preferably about 0 to 50°C. The catalytic reduction with hydrogen can be carried out in a solvent, such as water, methanol, ethanol, dimethylformamide, tetrahydrofuran, dioxane or the like, in the presence of a catalyst, which may for example be a palladium catalyst, rhodium catalyst or Raney nickel catalyst, at a temperature of about -10°C to 100°C, preferably about 20 to 50°C, under the hydrogen pressure of 1 to 10 atmospheres, preferably 1 to 5'.atmospheres, if necessary in the presence of an acid. The acid includes mineral acids (e.g. hydrochloric acid, nitric acid, phosphoric acid, hydrobromic acid) or organic acids (e.g. acetic acid, propionic acid, tartaric acid, benzoic acid, methanesulfonic acid, toluenesulfonic acid).
Compounds of formula (Ih) wherein D, R2, R3, R8, m and p are respectively as defined hereinbefore can each be produced by treating a compound of formula (Ig) with an acid or a base. Thus, compound (Ie) is treated with an aqueous solution of mineral acid (e.g. nitric acid, hydrochloric acid, hydrobromic acid, iodic acid, sulfuric acid) or an alkali metal hydroxide (e.g. sodium hydroxide, potassium hydroxide, barium hydroxide, lithium hydroxide) at a temperature of generally 10 to 150°C and preferably 50 to 100°C. The strength of the acid or base may be 1 to 10N and preferably 4 to 10N. The acid or the base is used in a proportion of about 20 to 40 equivalents relative to compound (Ig). Though it depends on reaction temperature, the reaction time is about 1 to 24 hours and preferably about 2 to 10 hours.
Compounds of formula (Ii) wherein Rj, R2, Ra, p and m are respectively as defined hereinbefore can be produced by reacting, for example, a compound of formula (VII) wherein Rrand m are as defined above with, for exampley a compound of formula (VIII) O{ (VIII) wherein R2, R3, p and X are respectively as defined hereinbefore and subjecting the reaction product to dehydration reaction.
The reaction between compounds (VII) and (VIII) can be conducted in an aprotic solvent, such as ethyl ether, tetrahydrofuran, dioxane or the like, using an alkyllithium (e.g. n-butyllithium, isobutyllithium, etc.) at a temperature of generally about -78°C to 20°C and preferably about -78 to -50°C. Generally, about 1 to 4 moles, preferably 1 to 1.5 moles, of compound (VII) is used to each mole of compound (VIII).
The dehydration reaction can be conducted in a solvent selected from among the common solvents which do not interfere with the reaction, such as aromatic solvents, e.g. benzene, toluene, xylene, etc. and ether solvents, e.g. tetrahydrofuran, dioxane, etc., if necessary in the presence of an acid catalyst such as toluenesulfonic acid, concentrated sulfuric acid, etc. at an elevated temperature of 50 to 150°C. This reaction may also be conducted by heating the material compound in a mineral acid (e.g. nitric acid, hydrochloric acid, hydrobromic acid, sulfuric acid) at 50 to 110°C.
Compounds of formula (Ij) (, HN wherein R2, R3, p and m are respectively as defined hereinbefore can be produced by treating a compound of formula (Ii) with an acid or a base or reducing the same compound (Ii) by a per se known method. The acid or base which is used in the above treatment of compound (Ii) includes, among others, mineral acids (e.g. nitric acid, hydrochloric acid, hydrobromic acid, iodic acid, sulfuric acid, etc.) or alkali metal hydroxides (e.g. sodium hydroxide, potassium hydroxide, barium hydroxide, lithium hydroxide, etc.). This treatment can be carried out in an aqueous solution of such acid or base at a temperature of 10 to 150°C, preferably 50 to 100°. The strength of said acid or base may be about 1 to 10N and is preferably about 4 to 10N. Based on compound (Ij), the acid or the base is used generally in a proportion of about 20 to 40 equivalents. Though it depends on reaction temperature, the reaction time is generally about 1 to 24 hours and preferably about 2 to 10 hours.
Regarding the per se conventional method for reducing compound (lj), the solvent may be any of the common solvents for organic reactions, such as water, methanol, ethanol, dimethylformamide, tetrahydrofuran, dioxane, etc., and the reaction can be conducted in such a solvent in the presence of a palladium, rhodium, platinum, Raney nickel or other catalyst at a temperature of about -10 to 100°C, preferably about 20 to 50°C, under the hydrogen pressure of 1 to 100 atmospheres, preferably 1 to 5 atmospheres, if necessary in the presence of an acid. The acid mentioned just above may be a mineral acid (e.g. hydrochloric acid, nitric acid, phosphoric acid, hydrobromic acid) or an organic acid (e.g. acetic acid, propionic acid, tartaric acid, benzoic acid, methanesulfonic acid, toluenesulfonic acid).
Compounds of formula (Ik) ς HN wherein A, R2, R3, p and m are respectively as defined hereinbefore can each be produced by subjecting a compound of formula (Ic) or (Id) to a dehydration reaction.
This dehydration reaction can be conducted in any of the common solvents which do not interfere with the reaction, such as aromatic solvents, e.g. benzene, toluene, xylene, etc. and ether solvents, e.g. tetrahydrofuran, dioxane, etc., at an elevated temperature of 50 to 150°C, if necessary in the presence of an acid catalyst such as toluenesulfonic acid, concentrated sulfuric acid and so on. The reaction can also be carried out by heating the mixture at 50 to 110°C in a mineral acid (e.g. sulfuric acid, hydrochloric acid, hydrobromic acid, sulfuric acid, etc.).
Compounds of formula (12) (, R/H wherein R/ has the same meaning as the above definition of Ri excepting a hydrogen atom, that is to say a hydrocarbon residue which may be substituted or an acyl group which may be substituted, and R2, R3/ A, m and p are respectively as defined hereinbefore can each be produced by reacting a compound of the formula (Ib), (Id), (Ie), (Ih), (Ij) or (Ik) with a compound of formula (IX) R.'X (IX) wherein R/ and X are as defined above.
The reaction of compound (Ib), (Id), (Ie), (Ih), (Ij) or (Ik) with compound (IX) can be conducted in any of the common solvents for chemical reactions, i.e. a protic solvent (e.g. water, methanol, ethanol, propanol, etc.) or an aprotic solvent (e.g. ethyl ether, tetrahydrofuran, dioxane, dimethylformamide, acetonitrile) at a temperature of generally -10 to 200°C and preferably 20 to 100°C.
Il -necessary, this reaction can be conducted in the presence of an organic base, such as pyridine, 4dimethylaminopyridine, triethylamine, triethylenediamine, tetramethylethylenediamine, etc., an inorganic base, such as sodium hydrogen carbonate, potassium hydrogen carbonate, sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, etc., or a metal hydride, such as sodium hydride, potassium hydride and so on. Based on each mole of compound (Ib), (Id), (Ie), (Ih), (Ij) or (Ik), the compound of formula (IX) is used in a proportion of generally about 1 to 10 moles and preferably about 1 to 2 moles. The reaction time is generally about 1 to 48 hours and preferably about 1 to 10 hours.
Therefore, particularly, among the compounds (I), Compounds (I') can be produced by 1) reacting a compound of the formula R7' -N^-(CH2)£-C-(^yY dV’) wherein M is as defined above, R7' is an acyl and Y is a halogen which can be obtained by reacting a compound of the formula r;-n (CH2)a-C-X wherein R7' and M are of the same meaning as defined above and X is a halogen with a compound of the formula (III1) wherein Y is of the same meaning as defined above, with a compound of the formula (V) wherein·-R2 and R3 are as defined above to obtain a compound of the formula r;-Oich^-)O wherein all the symbols are as defined above 2) treating a compound of the formula (la') as defined above with a acid or a base to obtain a compound of the formula (lb·) ; wherein all the symbols are as defined above 3) reducing a compound of the formula (la') as defined above to obtain a compound of the formula OH wherein all the symbols are as defined above. 4) treating a compound of the formula (Ic') as defined above with an acid or a base or reducing a compound of the formula (lb') defined above to obtain a compound of the formula OH wherein all the symbols are as defined above, ) reducing a compound of the formula (la') or (Ic') as defined above to obtain a compound of the formula wherein all the symbols are as defined above. 6) treating a compound of the formula (Ie') as defined above with an acid or a base to obtain a compound of the formula HN (CH2)£+1 (If) or wherein all the symbols are as defined above, 7) reacting a compound of the formula (Ib'), (Id') or (If') as defined above with a compound of the formula R/’X (IX) wherein Rj and X are as defined above to obtain a compound of the formula wherein all the symbols are as defined ‘above.
The specific conditions for the respective reactions 1) - 7) are as described hereinbefore in connection with the method of production of the compounds (la), (Ib), (Ic), (Id), (Ie), (If) and (I£).
As demonstrated in the test examples as mentioned below, the cyclic amine compounds (I), particularly compounds (I'), and salts of the present invention exhibit potent antihypoxic activity in mice and brain antiedematic activity in rats.
The clinical conditions or diseases in which the cyclic amine compound (I) and salt of the present invention may be indicated include, among others, various symptoms associated with cerebral hypoxia and ischemia, various symptoms associated with elevation of intracranial pressure due to neoplasmic or traumatic compression, and other diseases such as cerebral edema, acute symptons and sequelae of cerebral apoplexy, impaired consciousness and dementia. Therefore, the cyclic amine compound (I) and salt of the invention can be used in the prevention and treatment of these symptoms and diseases .
Thus, the present invention provides a useful therapeutic drug for acute symptoms in cerebral apoplexy or sequelae of cerebral apoplexy, particularly a therapeutic drug for cerebral edema and a brain/nerve cell protecting drug.
For use of the compound of the invention in the treatment of acute symptoms in cerebral apoplexy and disturbance of microcirculation in the brain (e.g. increase in erythrocyte deformability), or the prevention and treatment of sequelae of cerebral apoplexy, and a protection of neuronal cell death or the like, including the therapy of cerebral edema, it can be administered orally or parenterally to mammals including man in various dosage forms, e.g. tablets, granules, capsules, injections and suppositories. The dosage depends on the type of disease, condition, and other factors. However, the usual adult dosage is generally 0.1 mg - 3 g daily, preferably 0.3 - 300 mg daily, and most desirably 3 - 50 mg daily for administration by injection, or preferably 1 mg - 1 g and most desirably 10-300 mg for oral administration.
Some of the compounds, for example compounds (I) and their salts of the invention act on the central nervous system of mammals, where they exert potent anticholinesterase activity to show an excellent antiamnesic action against various types of induced amnesia in man and animals (e.g. mice).
Compared with physostigmine, a known cholinesterase antagonist, these compounds are characterized by a distinct separation of its action on central nerves from that on peripheral nerves, scarcely producing peripheral nervous symptoms such as spasm, salivation and diarrhea, if any, at antiamnesically effective doses and being long-acting and low in toxicity. Moreover, these compounds produce remarkable effects on oral administration.
Therefore, the compound of the invention is useful as a brain, function improving agent for mammals including man.
The diseases in which the compound of the invention may be indicated are, for example, senile dementia, Alzheimer's disease, Huntington's chorea, hyperkinesia and mania. The compound can be used in the prevention or treatment of these diseases.
In employing the compound of the invention as a brain function improving agent, it can be administered orally or parenterally to mammals including man in various dosage forms, e.g. tablets, granules, capsules, injections and suppositories. Although the dosage differs according to the type of disease, condition, etc., the usual daily adult dose is about 0.001-100 mg, preferably about 0.01-30 mg, and most desirably about 0.3-10 mg.
The following working, preparation and test examples are all intended to illustrate the invention in further detail and should by no means be construed as defining the metes and bounds of the invention.
The abbreviations used in the following description have the meanings defined below: Ac: acetyl, Bz: benzoyl, Bzl: benzyl, Cbz: benzyloxycarbonyl, 0/: phenyl The term 'room temperature' means about 10 to 30°C. l-Acetvl-4-f 4-piperidinobenzoyl)ciperidine A mixture consisting of 3.73 g of l-acetyl-4-(4fluorobenzoyl)piperidine and 3.0 ml of piperidine was stirred at 100°C for 24 hours and the reaction mixture was then dissolved in 100 ml of ethyl acetate. The solution was washed with a saturated aqueous solution of sodium hydrogen carbonate and water in that order and the organic layer was dried over anhydrous magnesium sulfate. The solvent was then removed and the residue was recrystallized from ethyl acetatehexane to give 3.7 g of the title compound as colorless crystals melting at 122-125°C.
Elemental analysis C19H26N2O2 Calcd.: C, 72.58; H, 8.34; N, .8.91 Found : C, 72.61; N, 8.28; N, 8.73 Example 2 1—Acetyl —4 — (4-morpholinobenzoyl) piperidine A mixture consisting of 3.73 g. of l-acetyl-4-(4fluorobenzoyl)piperidine and 2.6 ml of morpholine was stirred at 100°C for 24 hours and the reaction mixture was then dissolved in 100 ml of ethyl acetate. The solution was washed with a saturated aqueous solution of sodium hydrogen carbonate and water in that order and the organic layer was dried over anhydrous magnesium sulfate. The solvent was then removed and the residual oil was purified by silica gel column chromatography (eluent: methanol:dichloromethane = 1:19, v/v) to give 2.4 g of the title compound as oil.
Elemental analysis C18H24N2O3 Calcd.: C, 68.33; H, 7.65; N, 8.85 Found : C, 68.49; H, 7.54; N, 8.53 Example 3 l-Carbobenzoxy-4-(4-pyrrolidinobenzoyl) piperidine A mixture consisting of 4.1 g of l-carbobenzoxy-4(4-fluorobenzoyl)piperidine and 8 ml of pyrrolidine was p διύ stirred at 100°C for 24 hours and the reaction mixtures was then worked up in the same manner as Example 2 to give 3.2 g of the title compound as oil.
Elemental analysis C24H28N2O3 5 Calcd.: C, 73.44; H, 7.20; N, 7.14 Found : C, 73.19; H, 7.16; N, 7.23 Example 4 The compounds shown in Table 1 were synthesized in substantially the same manner as Example 2 or 3. Ο Ri -N Table 1 Compound No. Reaction process R , R 8 1 2 Ac n/>1 10 2 2 Ac ffjH „/CH3 3 2 AcXCII2 /CHa 4 2 -· Ac \h, 15 5 3 Cbz o 6 3 Cbz O // R.
Molecular formula Elemental analysis Calcd.
(Found) Appearance Oil C 2 β II 3 2 N 2 0 2 c 77. 19 (77. 32 II 7. 97 7. 96 N 6. 92 6. 94) II C25H3 I N 3 0 2 74. 04 (74. 15 7. 71 7. 73 10. 36 10. 15) II CiillzeNiOi 75. 40 (75. 35 7. 48 7. 25 7. 99 7. 78) 132-133*C (mp) C16H22N2O2 70. 05 (70. 13 8. 08 7. 94 10. 2 10. 31) Oil C25H3oN203 73. 86 (7 3. 9 5 7. 44 7. 17 6. 89 6. 86) II C 2 6 H3 2 N 2 03 74. 26 (74. 27 7. 67 7. 37 6. 66 6. 52) Compound Reaction R No.' process . 2 Ac 8 2 Ac 9 2 Ac 2 Ac 2 Ac 2 Ac Re ’Appearance <EtXEL :111-113°C (mp) x(CH2)2CH3x(CH2)2CH3 Oil H NCHa Oil II NCH2 Φ Oil H NCH2CH3 Oil o Oil Oil Ac . n Elemental analysis Molecular formula C 1 8 II 2 6 N 2 0 2 Calcd.. N 9. 2 6 9. 13) c 71. 49 (71. 46 (Found) II 8. 67 8. 49 C2oH3oN202 72. 69 (72. 72 9. 15 9. 10 8. 48 8. 57) Ci 5H20^2^2 69. 20 (69. 28 7. 74 7. 51 10. 76 10. 65) C 21 H 2 + N 2 0 2 74. 97 (74. 63 7. 19 7. 02 8. 33 8. 17) C I 6 H 2 2 N 2 0 2 70. 04 (69. 90 8. 08 8. 14 10. 17 10. 21) C.elh^NtOx 71. 97 (71. 86 8. 05 8. 06 9. 33 9. 49) C20H28M202 73. 14 (73. 05 8. 59 8. 30 8. 53 8. 32) AcN l-Acetyl-4-f 2,4-di(piperidino)benzoyl1piperidine A mixture consisting of 2.67 g of l-acetyl-4-(2,4difluorobenzoyl)piperidine and 5.0 ml of piperidine was stirred at 100°C for 24 hours and the reaction mixture was then worked up in the same manner as Example 2 to give 3.3 g of the title compound as oil.
Elemental analysis C24H35N3O2 Calcd.: C, 72.51; H, 8.87; N, 10.57 Found : C, 72.32; H, 8.63; N, 10.58 Example 6 Bzl Bz I l-Acetyl-4-f2,4-diΓ(4benzyl)piperidino1 benzoyl1piperidine A mixture consisting of 2.67 g of l-acetyl-4-(2,4difluorobenzoyl)piperidine and 8.8 ml of 4benzylpiperidine was stirred at 100°C for 24 hours and the reaction mixture was then worked up in the same manner as Example 2 to give 4.1 g of the title compound as oil. Elemental analysis C38H47N3O2 Calcd.: C, 78.99; H, 8.20; N, 7.27 Found : C, 79.10; H, 8.39; N, 7.15 Example 7 Ac l-Acetvl-3-(4-piperidinobenzoyl) piperidine A mixture consisting of 3.73 g of 1-acetyl-3-(4fluorobenzoyl) piperidine and 5 ml of piperidine was stirred at 100°C for 24 hours and the reaction mixtur^ was then worked up in the same manner as Example 1.
The residue was recrystallized from ethyl ether-nhexane to give 3.2 g of colorless crystals melting at 116-120°C.
Elemental analysis Ci9H28N2O2 Calcd.: C, 72.58; H, 8.34; N, 8.91 Found : C, 72.52; N, 8.06; N, 8.73 Example 8 • 2HC1 4-(

Claims (21)

1. A cyclic amine compound of the formula wherein 3 means a group of the formula: ^7TT\ 8 ’V7 or S(J) wherein Rq is (Ϊ) a hydrogen atom, © a Ci„5 alkyl, C 2 _ 4 alkenyl or C 2 _4 alkynyl group which may be substituted by a halogen, Ci_3 alkoxy, cyano, amino, mono- or di—Cj_g alkylcimino, 5- to 7-membered cyclic amino or hydroxy, an aryl group selected from phenyl and naphthyl or an aralkyl group selected from'benzyl , di phenyl methyl , phenylethyl, naphthylmethyl and naphthylethy1 which may be substituted on the ring by one to three substituents selected from the group consisting of a Cj_3 alkoxy, C^_3 alkyl, cyano, amino, mono- or di- Cj_g alkylamino, 5- to 7-membered cyclic amino, hydroxy, nitro and halogen and on the alkyl moiety of - the aralkyl group may be substituted by oxo or hydroxy, or ' ©a C 2 _g alkylcarbonyl, C 2 _g alkyloxycarbonyl or benzyloxycarbonyl which may be substituted by one to three substituents selected from the group consisting of a halogen, amino and primary or secondary amino having Cj_g alkyl substituent(s), mis 0, 1 or 2; A means a bond or a two- or three-valent aliphatic hydrocarbon residue which may be substituted by hydrocarbon residues, oxo, hydroxyimino, and/or‘hydroxy; . means either.a single bond or a double bond (provided that when A means a bond,..;. means a single bond); R 2 and R3 independently mean (Ϊ) a hydrogen atom, (2) a Cx.g alkyl, C2-4 alkenyl or C2-4 alkynyl group which may be substituted by a· halogen, Ci_3 alkoxy, cyano, amino, mono- or di-C]__g alkylamino, 5-' to 7-membered cyclic amino or hydroxy, or (3) an aryl group selected from phenyl and naphthyl or an aralkyl group selected from benzyl, diphenylmethyl, phenylethyl, naphthylmethy! and naphthylethy1 which may be substituted on the ring by one to three substituents selected from the group consisting of a C^_3 alkoxy, Cj_3 alkyl, cyano, amino, mono- or di- Cj_g alkylamino, 5- to7-membered cyclic amino, hydroxy, nitro and halogen and on the alkyl moiety of the aralkyl group may be substituted by oxo or hydroxy (provided that both of R2 and R3 are not hydrogen atoms) or jointly form a cyclic amino group together with the adjacent nitrogen atom; n is 0, -1 or 2 and p is ' 1 or 2 or a physiologically acceptable salt thereof.
2. A compound of claim 1 which is represented by the formula R wherein Ri“ is a hydrogen atom or a benzyl group which may be substituted on the ring by one to three substituents selected from the group consisting of a Ci_3 alkoxy, Ci_3 alkyl, cyano, amino, mono- or di-Cj_g alkylamino, 5- to 7-membered cyclic amino, hydroxy, nitro and halogen and on the methyl moiety of the benzyl group may be substituted by oxo or' hydroxy, £ is an integer of 0 to 4 and D' is a group of the formula -C-, -CH- or -CH a II I Ο OH and R2' and R 3 ' are independently ' a Ci_g alkyl group or jointly form a cyclic amino group together with the adjacent nitrogen atom.
3. A compound of claim 2 wherein the benzyl group denoted by R^, is unsubstituted or has one to three substituents selected from Cj. 3 alkoxy groups, C 3 . 3 alkyl groups, cyano, hydroxy, nitro and halogens.
4. A compound of claim 2 wherein R r is a hydrogen atom and 1 is 0.
5. A compound of claim 4 wherein D' is a croup of the formula -CH 2 -.
6. A compound of claim 2 wherein R 2 f and R 3 ' are methyl groups .
7. A compound of claim 4 wherein R 2 ' and R 3 ' are methyl groups.
8. A compound of claim 2 wherein Rj is a benzyl group and D' is a group of the formula
9. A compound of claim 8 wherein ί is 2.
10. A compound of claim 8 wherein R 2 ' and R 3 ' are methyl groups or jointly form, together with the adjacent nitrogen atom, a piperidino group, pyrrolidino group or morpholino group.
11. A compound of claim 1 of the formula C O< wherein R 2 and R 3 are as defined
12. A method for the production in claim 1. of a compound of the formula Ri * -0(CH : ) 1 Ο’Ο-Νζ (I') wherein all the symbols are of the same meaning as defined above in claim 2 Or a salt thereof which is characterized by •1) reacting a compound of the formula R,' -Ν^χ- (CHj) (IV ' 5 0 ~ wherein 2 is as defined above, R 7 ' is an acyl and Y is a halogen which can be.obtained by reacting a compound of the formula R,-N (II') wherein R 7 ' and 2 are of the same meaning -as defined above and X is· a -halooen with a compound of the formula (III 1 ) wherein Y is of the same meaning as defined above, with a compound of the formula HN / R 2·» * (V) wherein R 2 ' and R 3 ' are as defined above to obtain a compound of the formula A” (la ’) wherein all the symbols are as defined above; 2. ) treating a compound of the formula (la') as defined above with a acid or a base to obtain a compound of the formula· wherein all the symbols are as def-ined above; 3. ) reducing a compound of the formula (la') as defined above to obtain a compound of the formula wherein all the symbols are as defined above; 4. ) treating a compound of the formula (Ic') as defined above with an acid or a base or reducing a compound of the formula (lb') defined above to obtain a compound of the formula )I-CH I OH “> wherein all the symbols are as defined above; 5. ) reducing a compound of the formula (la') or (Ic') as defined above to obtain a compound of the formula (Ie’) wherein all the symbols are as defined above; 5) treating a compound of the formula (Ie') as defined above with an acid or a base to obtain a compound of the formula wherein all the symbols are as defined above or 7) reacting a compound of the formula (lb'), (Id') or (If') as defined above in 2) or 4) respectively with a compound of the formula RiX (IX) wherein Ri and X. as. as defined above to obtain a compound of the formula wherein all the symbols are as defined 'above, if desired, followed by conversion to a salt thereof.
13. A composition for use in treating cerebral edema and/or acute symptom in cerebral apoplexy which is characterized by containing a compound of claim 4.
14. A composition for use in protecting brain and nerve cell, characterized by containing a compound of claim 4.
15. A composition for use in inhibiting cholinesterase, characterized by containing a compound of claim 3.
16. A composition for use in improving a brain function, characterized by containing a compound cf claim 3.
17. A composition for use in treating disturbance of microcirculation in the brain, characterized by containing a compound of claim 4.
18. A cyclic amine compound of the formula given and defined in claim 1 or a physiologically acceptable salt thereof, which is any one of those specifically hereinbefore mentioned.
19. A method for the production of a cyclic amine compound of the formula given and defined in claim 1 or a physiologically acceptable salt thereof, substantially as hereinbefore described and exemplified.
20. A cyclic amine compound of the formula given and defined in claim 1 or a physiologically acceptable salt thereof, whenever produced by a method claimed in a preceding claim.
21. A composition according to any one of claims 13-17, substantially as hereinbefore described and exemplified .
IE14290A 1989-01-13 1990-01-12 Cyclic amine compounds and their use IE63302B1 (en)

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